KR20090085067A - Pharmaceutical composition containing naphthoquinone-based compound for intestine delivery system - Google Patents

Abstract

A pharmaceutical composition for intestine delivery system containing naphthoquinone compound is provided to raise the absorption in a body and enhance the lasting time in the body. A pharmaceutical composition for intestine delivery system is produced by formulating a naphtoquinone compound of the chemical formula 1, pharmaceutically allowable salt, prodrug, solvent compound or isomer. In the chemical formula 1, R1 and R2 are separately hydrogen, halogen, alkoxy, hydroxyl or low alkyl of 1-6 carbon atoms; R3, R4, R5, R6, R7 and R8 are separately hydrogen, hydroxyl, alkyl of 1-20 carbon atoms, alken or alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or circular structure by bonding between two substitutes.

Description

Pharmaceutical composition for enteric target containing naphthoquinone type compound {PHARMACEUTICAL COMPOSITION CONTAINING NAPHTHOQUINONE-BASED COMPOUND FOR INTESTINE DELIVERY SYSTEM}

The present invention relates to a pharmaceutical composition for enteric targeting containing a naphthoquinone compound, and more particularly, to a specific naphthoquinone compound, a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof as an active material. Provided is a pharmaceutical composition for oral administration formulated in an Intestine delivery system.

It has recently been confirmed by the applicant that certain naphthoquinone compounds are useful for the treatment and prevention of metabolic diseases (see Korean Patent Application Nos. 2004-0116339 and 2006-14541).

However, the naphthoquinone compounds dissolve only in small amounts (approximately 2 to 10%) in solvents with excellent solubility, such as CH ₂ Cl ₂ , CHCl ₃ , CH ₂ ClCH ₂ Cl, CH ₃ CCl ₃ , Monoglyme, Diglyme, and other general polarities. Or poorly soluble materials that do not dissolve well in nonpolar solvents, despite the excellent pharmacological effects, there are many difficulties in formulating for in vivo administration.

Currently, the naphthoquinone-based compound having high solubility is significantly limited in formulation, and although the physiological activity of the naphthoquinone-based compound has been revealed by the applicant, the form of the formulation is determined by the administration of the body by vascular injection. It is limited.

Naphthoquinone compounds, which are poorly soluble drugs, when taken orally by themselves or in general simple formulations, are hardly absorbed by the body, that is, because of their very low bioavailability, they do not show the inherent drug efficacy.

This fact is supported by recent research by Jing et al. And reported that the absorption rate by oral administration of Cryptotansinone, which is a kind of naphthoquinone compound, is very low at 2.05%. The cause is known to be due to the poorly soluble drug properties and the use of PgP as a substrate, so first-pass problems have a significant effect on absorption (Journal of pharmacology & Experimental Therapeutics 23, 2006).

On the other hand, a drug containing a naphthoquinone compound as an active material only exhibits its efficacy only when a certain concentration or more is absorbed into the body. Many factors are involved in the bioavailability, which means the degree of drug available in the target tissue after administration, and the low bioavailability causes serious problems in drug composition development.

Therefore, in order to properly utilize the inherent weaknesses of naphthoquinone compounds, introduction of methods for maximizing the bioavailability of these drugs is urgently needed.

Technical challenge

The present invention aims to solve the problems of the prior art as described above and the technical problems that have been requested from the past.

When the poorly soluble naphthoquinone-based compound is formulated for enteric targets, the inventors of the present application can minimize the inactivation of the active material by the internal environment such as the stomach, and problems of low bioavailability caused by general oral administration. It is possible to solve the problem, through which it was found that the pharmacokinetic properties of the naphthoquinone-based compound can be significantly improved and came to complete the present invention.

Technical solution

Accordingly, the present invention is for oral administration characterized in that the naphthoquinone-based compound represented by the following formula (1), a pharmaceutically acceptable salt, prodrug, solvate or isomer thereof as an active material is formulated for enteric targets Provide a pharmaceutical composition.

Where

R ₁ and R ₂ are each independently hydrogen, halogen, hydroxy, lower alkyl or alkoxy having 1 to 6 carbon atoms;

R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently hydrogen, hydroxy, alkyl having 1 to 20 carbon atoms, alkene or alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Or two of these substituents may form a cyclic structure by mutual bonding, wherein the cyclic structure may be a saturated structure or a partially or wholly unsaturated structure;

X is selected from the group consisting of C (R) (R '), N (R "), O and S, preferably O, where R, R' and R" are each independently hydrogen or 1 to 6 carbon atoms Lower alkyl of;

n is 0 or 1, and when n is 0, its adjacent carbon atoms form a cyclic structure by direct bond.

As used herein, the term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like, tartaric acid, formic acid, citric acid Sulfonic acids such as acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, organic carbonic acid such as fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by phonic acid or the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine and the like. The compounds according to the invention can also be converted to their salts by conventional methods.

The term "prodrug" refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial. Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group that is converted by metabolism to reveal the active site.

As an example of such a prodrug, the pharmaceutical composition according to the present invention may include a prodrug of Formula 1a as an active material.

Where

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , X and n are the same as in formula (1);

R ₉ and R ₁₀ are each independently —SO _{3 —} Na ⁺ or a substituent or a salt thereof represented by the following Chemical Formula 2,

Where

R ₁₁ and R ₁₂ are each independently hydrogen or substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl,

R ₁₃ is selected from the group consisting of the following substituents iii) to iii),

Iii) hydrogen;

Ii) substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl;

Iii) substituted or unsubstituted amine;

Iii) substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ heterocycloalkyl;

Iii) substituted or unsubstituted C _{4 to} C ₁₀ aryl or C _{4 to} C ₁₀ heteroaryl;

Iii)-(CRR'-NR "CO) _1- R ₁₄ , wherein R, R 'and R" are each independently hydrogen or substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl, R ₁₄ May be selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and 1 is selected from 1 to 5;

Iii) substituted or unsubstituted carboxyl;

Iii) -OSO _3- Na ⁺ ;

k is selected from 0 to 20, and when k is 0, R ₁₁ and R ₁₂ are not present and R ₁₃ is directly bonded to a carbonyl group.

The term "solvate" includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. It means a compound of the present invention or a salt thereof. Preferred solvents in this regard are solvents which are volatile, non-toxic, and / or suitable for administration to humans, and when the solvent is water, it means hydrate.

The term "isomer" means a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but which is optically or sterically different. For example, D-type and L-type optical isomers may be present depending on the selection of the R ₃ to R ₈ substituent group in Chemical Formula 1.

Unless stated otherwise, the term "naphthoquinone-based compound" is used in the concept including the compound itself, pharmaceutically acceptable salts, prodrugs, solvates and isomers thereof.

The term "alkyl" refers to an aliphatic hydrocarbon group. In the present invention, alkyl means "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety, and "unsaturated alkyl" means that it contains at least one alkene or alkyne moiety. It is used as a concept that includes all of them. "Alkene" moiety means a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and an "alkyne" moiety means at least two carbon atoms having at least one carbon-carbon triple bond Means a group. The alkyl may be branched, straight chain or cyclic, and may be substituted or unsubstituted.

The term "heterocycloalkyl" is a substituent in which the ring carbon is substituted with oxygen, nitrogen, sulfur, and the like, for example, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, Imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, Although pyrimidine, pyrazine, piperazine, triazine, etc. are mentioned, It is not limited to these.

The term "aryl" refers to aromatic substituents having at least one ring having a shared pi electron system and comprising carbocyclic aryl (eg phenyl) and heterocyclic aryl (eg pyridine) it means. The term includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups.

The term "heteroaryl" refers to an aromatic group containing at least one heterocyclic ring.

Examples of the aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, and the like.

In Formula 1 according to the present invention, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ may be an optionally substituted structure, and examples of such substituents include cycloalkyl, aryl, Heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thio Carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, iso One or more substituents individually and independently selected from thiocyanato, nitro, cyryl, trihalomethanesulfonyl, amino including mono- and di-substituted amino groups, and protective derivatives thereof, and the like. have.

Preferred examples of the compound of Formula 1 may be a compound of Formulas 3 and 4.

The compound of formula 3 is a compound in which n is 0 and adjacent carbon atoms form a cyclic structure (furan ring) by direct bonding, sometimes referred to as 'furan compound' or 'furano-o-naphthoquinone derivative' .

The compound of formula 4 is n is 1, hereinafter sometimes referred to as 'pyran compound' or 'pyrano-o-naphthoquinone'.

In Formula 1, R ₁ and R ₂ are particularly preferably hydrogen.

Particularly preferred examples of the furan compounds of Formula 3 include a compound of Formula 3a, wherein R ₁ , R _2, and R ₄ are each hydrogen, or a compound of Formula 3b, wherein R ₁ , R _2, and R ₆ are each hydrogen: Can be mentioned.

In addition, particularly preferred examples of the pyran compounds of the formula (4) include a compound of formula (4a) wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and R ₈ are each hydrogen.

The term "pharmaceutical composition" refers to a mixture of the compound of formula 1 as the active material and other ingredients necessary for the formulation of the enteric target.

Preparation of Active Material

The compounds of Formula 1, which are active materials in the pharmaceutical composition according to the present invention, may be prepared by various methods based on known methods and / or techniques of organic synthesis, as described below. Are only some examples, and other methods may be present.

Preparation Method 1: Synthesis of Active Material by Acid Catalytic Cyclization Reaction

Generally, tricyclic naphthoquinone (pyrano-o-naphthoquinone and furano-o-naphthoquinone) derivatives of relatively simple structure are synthesized in a relatively good yield through a cyclization reaction using sulfuric acid as a catalyst. Compounds can be synthesized.

These processes can be summarized in more general chemical equations as follows.

That is, when 2-hydroxy-1,4-naphthoquinone is reacted with various allylic bromide or its equivalents in the presence of a base, a substance having C-alkylation and O-alkylation reactions is obtained together. Depending on the reaction conditions, it is also possible to synthesize only one derivative. Here, O-alkylated derivatives are converted to another type of C-alkylated derivative through the Claisen Rearrangement reaction by refluxing with a solvent such as toluene or xylene, so that various types of 3-substituted-2-hydroxy-1, 4-naphthoquinone derivatives can be obtained. The various types of C-alkylated derivatives thus obtained may synthesize pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives among the compounds of Formula 1 by inducing a cyclization reaction using sulfuric acid as a catalyst.

Preparation Method 2: Diels-Alder Reaction Using 3-methylene-1,2,4- [3H] naphthalenetrione

V. Nair et al. {Tetrahedron Lett. 42 (2001), 4549-4551}, the various olefins of 3-methylene-1,2,4- [3H] naphthalenetrione produced when 2-hydroxy-1,4-naphthoquinone is heated with formaldehyde. It has been reported that various pyrano-o-naphthoquinone derivatives can be synthesized relatively easily by inducing Diels-Alder reaction with compounds. This method has the advantage of being able to synthesize various types of pyrano-o-naphtho-quinone derivatives relatively simply compared to reactions that induce cyclization under sulfuric acid catalyst conditions.

Preparation Method 3: Haloakylation and Cyclization by Radical Reaction

The methods used for the synthesis of Cryptotanshinone and 15,16-Dihydro-tanshinone can also be conveniently used to synthesize furano-o-naphthoquinone derivatives. As described by AC Baillie et al. (J. Chem. Soc. (C) 1968, 48-52), a 2-haloethyl or 3-haloethyl radical species derived from 3-halopropanoic acid or 4-halobutanoic acid derivatives are known. By reacting with 2-hydroxy-1,4-naphthoquinone, 3- (2-haloethyl or 3-halopropyl) -2-hydroxy-1,4-naphthoquinone can be synthesized, which induces cyclization under appropriate acidic catalytic conditions. Thus, various pyrano-o-naphthoquinone or furano-o-naphthoquinone derivatives can be synthesized.

Preparation Method 4: Cyclization Reaction by Diels-Alder Reaction of 4,5-Benzofurandione

Another method used for the synthesis of Cryptotanshinone and 15,16-Dihydro-tanshinone is JK Snyder et al. (Tetrahedron Letters 28 (1987), 3427-3430). There is a way to notice this. In this method, furano-o-naphthoquinone derivatives can be synthesized by inducing cycloaddition by Diels-Alder reaction between 4,5-Benzofurandione derivatives and various diene derivatives.

In addition, various derivatives can be synthesized using an appropriate synthesis method according to the type of substituents based on the above methods, and specific examples thereof are shown in Table 1 below. Specific preparation methods for these are described in the following examples.

TABLE 1

In general, the oral pharmaceutical composition passes through the stomach during oral administration, is mainly absorbed by the small intestine, and diffuses into the entire tissue, thereby exerting a pharmacological effect on the target tissue.

In this regard, the pharmaceutical composition for oral administration according to the present invention increases the amount of body absorption and bioavailability of a specific naphthoquinone-based active material, which is an active material, by formulation of an enteric target. Specifically, in the pharmaceutical composition according to the present invention, when the active material is mainly absorbed in the stomach, the small intestine, etc., the active material absorbed into the body immediately undergoes liver metabolism, and a small amount of the pharmacological effect is desired. If it is not absorbed, but is mainly absorbed after the lower part of the small intestine, the absorbed active material is expected to exert a high pharmacological effect by moving to the target tissue through the lymph and the like.

In addition, by targeting the colon, the final route of the digestion step, it is possible to increase the duration of the body and to minimize the degradation of the drug due to metabolism during administration in the body. This improves the kinetic properties of the drug, significantly lowers the critical dose of the active amount required for the treatment of the disease, and achieves the desired pharmacological effect only by administering a small amount of the active material. . In addition, in the pharmaceutical composition for oral administration, absorption variation can be minimized by reducing the difference in intrinsic pH in the stomach and the in-vivo utilization due to food intake.

Thus, the formulation for enteric targeting according to the invention means that the active material is absorbed in the small intestine and the large intestine, but more preferably the jejunum, the lower intestine the ileum and the colon, particularly preferably the ileum or It is configured to be absorbed primarily in the colon.

The enteric target formulation may be designed by a variety of methods using various physiological parameters of the digestive tract. In one preferred embodiment, the formulation for enteric targeting comprises (1) a formulation based on pH sensitive polymer, (2) a formulation based on biodegradable polymer by enteric specific bacterial enzymes, (3) Formulation schemes based on biodegradable matrices by specific bacterial enzymes, or (4) formulation schemes in which the drug is released after a certain lag time, and combinations thereof.

Specifically, the enteric targeted formulation (1) using the pH sensitive polymer is a drug delivery system based on the pH change of the digestive tract. The pH of the stomach is 1 to 3, and the pH in the small intestine and intestine increases compared to the pH of the stomach and maintains above 7, based on the fact that the pharmaceutical composition does not undergo changes in the pH of the digestive tract, PH sensitive polymers can be used to reach the bottom. The pH sensitive polymer may be, for example, one or two or more selected from the group consisting of methacrylic acid-ethyl acrylate-based copolymer (Eudragit®) and hydroxypropylmethylcellulose phthalate. It is not limited only to these.

The pH sensitive polymer may preferably be added via a coating, for example, by mixing the polymer in a solvent to form an aqueous coating suspension, spraying the coating suspension to form a film coating, and then applying a film coating. It may be made through a drying process.

The intestinal targeted formulation (2) using the biodegradable polymer by the intestinal specific bacterial enzyme utilizes the compound degrading ability of the specific enzyme that can be produced by the microorganisms present in the intestine. For example, it may be azoreductase or bacterial hydrolase glycosidase, esterase or polysaccharidase.

In the case of designing an intestinal targeted formulation targeting the azo reductase, the biodegradable polymer may be a polymer having an azo aromatic link, for example, styrene and hydroxyethyl methacrylate (HEMA). It may be a copolymer of. When the polymer is added to a formulation containing an active material, the active material is reduced by reducing the azo group of the polymer by an azo reductase specifically secreted by bacteria in the intestine, for example, Bacteroides fragilis and Eubacterium limosum . Can be liberated.

When the intestinal targeted formulation is designed by targeting the glycosidase, esterase or polysaccharide, the biodegradable polymer may be a polysaccharide or a substituent thereof, which is a natural substance. For example, it may be one or two or more selected from the group consisting of dextran esters, pectin, amylose and ethylcellulose or pharmaceutically acceptable salts thereof. When the polymer is added to the active material, bacteria present in the intestine, for example, Bifidobacteria and Bacteroides spp. The hydrolysis reaction takes place by each of the enzymes specifically secreted by and the like may release the active material into the intestine. These polymers are natural substances, and have the advantage of low toxicity.

The enteric targeted formulation 3 using the biodegradable matrix by the enteric specific bacterial enzyme may be in a form in which biodegradable polymers are cross-linked with each other and added to an active material or a formulation containing the same. The polymer may be, for example, a natural polymer such as chondroitin sulfate, guar gum, chitosan or pectin, and the amount of drug released may vary depending on the degree of crosslinking of the polymer constituting the matrix. have.

In addition to the natural polymer may be a synthetic hydrogel based on N-substituted acrylamide, for example, hydrogel or 2-hydroxyethyl methacrylate and 4-methacryloyl- synthetically prepared by cross-linking N-tert-butylacryl amide and acrylic acid Hydrogels prepared by hybrid polymerization of oxyazobenzene may be used as the matrix. The crosslinking can be, for example, the azo bonds mentioned above, and the density of the crosslinking maintains optimal conditions for adequately delivering the drug to the intestine, and when delivered to the intestine The bond can be in a form that can be broken down and interact with the intestinal mucosa.

Furthermore, the enteric targeted formulation (4) by the system in which the drug is released after a certain lag time has elapsed has a mechanism to allow the release of the active material after a predetermined delay time regardless of the change in pH environment. Used drug delivery system, in order to release the active material in the intestine, must resist the acid environment of the stomach, and before releasing the active ingredient in the intestine, silent for 5-6 hours, corresponding to the transport time from the human body to the intestine It must be in a silent phase. The delayed-time formulation can be made, for example, by addition of a hydrogel prepared by hybrid polymerization of polyethylene oxide and polyurethane.

Specifically, when the hydrogel of the composition is added after the drug is loaded on the insoluble polymer, it is swelled by water absorption while staying in the upper digestive tract of the stomach and small intestine, and moves to the lower digestive tract of the lower digestive tract to liberate the drug. The delay time of the drug may be a structure determined according to the length of the hydrogel.

As another example, ethylcellulose (EC) may be used in delayed time formulations. The EC is an insoluble polymer, and may act as a factor for delaying drug release time according to the influence of pressure change in the intestine due to swelling or peristalsis of the swelling medium due to water infiltration. It can be adjusted by the thickness of the EC. As another example, hydroxypropylmethylcellulose (HPMC) can also be used as a retarding agent to release the drug after a certain time through controlling the thickness of the polymer, the delay time is 5 ~ It can be about 10 hours.

In the pharmaceutical composition for oral administration according to the present invention, the active material may be in a form having a high crystallinity crystal structure, or may be in a form having a low crystallinity crystal structure.

The "degree of crystallinity" is the weight fraction of the crystal part relative to the whole compound, the measurement of the crystallinity can be carried out by a known method, for example, in advance the set value of the degree of addition and subtraction in the density of each of the crystal part and the amorphous part It can be performed by the density method or the fine needle method, which is assumed, and the crystallinity can be determined by the measurement method by the heat of fusion. Crystallinity can be measured by the X-ray method or the infrared method obtained from the peak of the crystalline band width of an infrared absorption spectrum.

In the pharmaceutical composition for oral administration according to the present invention, the crystallinity of the active material is preferably 50% or less, and more preferably, it may be an amorphous crystal structure in which the intrinsic crystallinity of the substance is completely lost. The amorphous naphthoquinone-based compound exhibits a relatively high solubility as compared to the crystalline naphthoquinone-based compound, and can significantly improve the dissolution rate and absorption in the body.

In one preferred example, the amorphous structure may be made in the process of preparing the active material into fine particles. The microparticles can be prepared by, for example, spray drying of an active material, a melting method of forming a polymer and a melt, a coprecipitation method of dissolving in a solvent to form a coprecipitation with a polymer, a clathrate formation method, and a volatilization of a solvent. Preferably, spray drying can be used. On the other hand, the fine particle formation of the active material by the mechanical grinding method, even if it is not an amorphous structure, that is, crystalline crystal structure or semicrystalline crystal structure, contributes to the solubility improvement by the large specific surface area and consequently the dissolution rate and absorption rate in the body Improvement can be aimed at.

The spray drying method is a method of preparing fine particles by dissolving the active material in a predetermined solvent and then spraying it to dry it. In the spray drying process, a significant amount of the crystallinity of the naphthoquinone compound itself is lost and becomes amorphous. Obtained.

The mechanical grinding method is a method of grinding into fine particles by applying a strong physical force to the particles of the active material, a grinding process such as jet mill, ball mill, vibrating mill, hammer mill, etc. may be used, under the conditions of 40 ℃ or less using air pressure Particular preference is given to jet mills which can carry out grinding.

On the other hand, regardless of the crystal structure, the active material in the form of fine particles increases the dissolution rate, solubility, etc. due to the increase in specific surface area as the particle size decreases, but too small particle size is not only easy to prepare microparticles of such size Since the solubility may be lowered due to the aggregation (agglomeration or aggregation) between the particles, in one preferred embodiment, the particle size of the active material may be in the range of 5 nm to 500 ㎛. In this range, the aggregation phenomenon can be suppressed to the maximum, and the dissolution rate and solubility can be maximized by the high specific surface area.

Preferably, a surfactant and / or an antistatic agent may be further added to prevent generation of static electricity in order to prevent agglomeration of particles during the microparticulation process.

In some cases, a predetermined absorbent may be further included in the grinding process. Since the naphthoquinone-based compound of Formula 1 tends to crystallize by water, by adding a hygroscopic agent, the naphthoquinone-based compound can be suppressed from recrystallization over time, and the solubility can be maintained due to microparticles. do. In addition, the hygroscopic agent serves to suppress entanglement and aggregation of the pharmaceutical composition without affecting the pharmacological effect of the active material.

Examples of the surfactant include anionic surfactants such as sodium docusate and sodium lauryl sulfate; Cationic surfactants such as benzalkonium chloride (Benzalkonium Chloride), benzetium chloride (Benzethonium Chloride), and cetrimide; Nonionic surfactants such as glycerin monooleate, polyoxyethylene sorbitan fatty acid esters, and sorbitan esters; Positive affinity polymers such as polyethylene-polypropylene polymer and polyoxyethylene-polyoxypropylene polymer (Poloxamer, Poloxamer), and other Gelucire ™; Monocaprylic Glycol Monocaprylate, Oleoyl Macrogol-6 Glyceride, Linoleoyl Macrogol-6-Glyceride Caprylocaproyl macrogol-8 Glyceride, Propylene Glycol Monolaurate, Polyglyceryl-6 Dioleate, and the like. However, the present invention is not limited thereto, and these may be used alone or in combination of two or more.

Examples of the hygroscopic agent include colloidal silica, hard silicic anhydride, heavy silicic anhydride, sodium chloride, calcium silicate, potassium aluminosilicate, calcium aluminosilicate, and the like, but are not limited thereto, and these are alone or two or more. It may be used in combination.

Some of the moisture absorbents may also be used as antistatic agents.

The surfactant, the antistatic agent, the moisture absorbent and the like are added in a predetermined amount that can exert the effects described above, and can be appropriately determined according to the micronization conditions. Preferably, the additives may be used in the range of 0.05 to 20% by weight based on the total weight of the active material.

In one preferred embodiment, the pharmaceutical composition according to the present invention may add a water-soluble polymer, a solubilizing agent and a disintegration accelerator in the process of formulating for oral administration, and preferably, The active material in the form of fine particles may be mixed and then spray-dried to be formulated.

The water-soluble polymer prevents agglomeration of active materials in the form of fine particles, converts naphthoquinone-based compound molecules or particles into hydrophilicity and ultimately increases solubility in water, and is preferably an amorphous of naphthoquinone-based compound as an active material. It helps to maintain the state of matter.

Such a water-soluble polymer is preferably a pH-independent polymer, and may have an effect of inducing crystalline loss of the active material and increasing hydrophilicity even under intrinsic pH variation of an individual or an individual gastrointestinal tract.

One preferred example of the water-soluble polymer is methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, hydroxy Cellulose derivatives such as propyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, sodium carboxymethyl cellulose, and carboxymethyl ethyl cellulose; Polyvinyl alcohol; Polyvinylacetate, polyvinylacetate phthalate, polyvinylpyrrolidone or a polymer comprising the same; It may be one or two or more selected from the group consisting of polyalkene oxide or polyalkenecol and a polymer comprising the same, and preferably hydroxypropylmethylcellulose.

In the pharmaceutical composition of the present invention, the content of the water-soluble polymer does not increase the solubility any more than a certain degree, the overall hardness of the formulation is increased, and the water-soluble polymer swells excessively when exposed to the eluate to form a film around the formulation. As a result, it was confirmed that there was a problem of blocking the penetration of the eluate into the formulation. Therefore, it is preferable to include a solubilizer to change the physical properties of the naphthoquinone-based compound to maximize the solubility of the formulation.

In such aspect, the solubilizer serves to promote solubilization and improve wettability of the poorly soluble naphthoquinone compound, and the bioavailability of the naphthoquinone compound resulting from the drug and time difference after ingestion of food and food. I can greatly alleviate my utilization variation. As such a solubilizer, a surfactant or amphophile which is generally widely used may be selected, and specific examples thereof may refer to the examples of the surfactant described above.

The disintegration accelerator improves the release rate of the drug and increases the rate of drug use in the body by allowing the drug to be rapidly eluted at the target site.

Preferred examples of such disintegration accelerators may be one or two or more selected from the group consisting of sodium croscarmellose, crospovidone, calcium carboxymethylcellulose, sodium starch glycolate and low-substituted hydroxypropyl cellulose, but these It is not limited to only, preferably may be croscarmellose sodium.

In consideration of various factors as described above, based on 100 parts by weight of the active material, the water-soluble polymer is added to 10 to 1000 parts by weight, the disintegration accelerator is 1 to 30 parts by weight, the solubilizer is added to 0.1 to 20 parts by weight, respectively. desirable.

In some cases, in addition to the above components, other substances known in the art with respect to the formulation may optionally be further added.

The solvent for the spray drying is a material that shows high solubility without changing the physical properties of these materials and is easily volatilized during the spray drying process, and preferably, dichloromethane, chloroform, methanol, ethanol, and the like, It is not limited, and they may be used alone or in combination of two or more. The concentration of such a spray liquid is preferably about 5 to 50% by weight solids content based on the total weight.

Formulation for enteric targets as described above may preferably be done for formulation particles prepared as above.

In one preferred embodiment, the pharmaceutical composition for oral administration according to the present invention,

(a) preparing an active material microparticle by grinding the naphthoquinone-based compound of Formula 1 alone or in a state where a surfactant and a moisture absorbent are added in a jet mill;

(b) dissolving the active material fine particles in a predetermined solvent together with a water-soluble polymer, a solubilizing agent and a disintegration accelerator, and then spray-drying to prepare a formulation particle;

(c) dissolving the formulation particles together with a pH-sensitive polymer and a plasticizer in a predetermined solvent, followed by spray drying to form an enteric target coating on the formulation particles;

It can be formulated in a process comprising.

The surfactant, the moisture absorbent, the water-soluble polymer, the solubilizing agent, the disintegration accelerator and the like are the same as described above, the plasticizer may be used as an additive for preventing the stiffening of the coating, for example, a polymer of polyethylene glycol.

In some cases, the active material particles pulverized with a jet mill in step (a) are seeded, and the excipient of step (b) and the enteric target coating materials of step (c) are sequentially or simultaneously. It can also be formulated by spraying.

The pharmaceutical composition for oral administration used in the present invention contains the active material in an amount effective to achieve its intended purpose, that is, the therapeutic purpose. In particular, a therapeutically effective amount means an amount of a compound effective to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

In addition, the compositions for oral administration according to the present invention are particularly effective for the treatment or prevention of metabolic diseases, degenerative diseases, and mitochondrial disorders. The metabolic disease may include, but is not limited to, obesity, obesity complications, liver disease, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, diabetes-related complications, inflammation, and the like.

Examples of the obesity complications include hypertension, myocardial infarction, varicose veins, pulmonary embolism, coronary artery disease, cerebral hemorrhage, dementia, Parkinson's type 2 diabetes, hyperlipidemia, stroke, cancer (uterine, breast, prostate, colon cancer, etc.), heart disease , Gallbladder disease, sleep apnea, arthritis, infertility, venous ulcer, sudden death, fatty liver, hypertrophic cardiomyopathy, thromboembolism, esophagitis, abdominal wall hernia, urinary incontinence, cardiovascular disease, high blood pressure, endocrine diseases.

Examples of the diabetes-related complications include hyperlipidemia, hypertension, retinopathy, renal failure, and the like.

Examples of the degenerative disease include Alzheimer's disease, Parkinson's disease, or Huntington's disease.

Examples of the mitochondrial disorders include multiple sclerosis, encephalomyelitis, cerebral myositis, peripheral neuropathy, Ly's syndrome, Friedrich's amnesia, Alper's syndrome, MELAS, migraine, psychosis, depression, seizures and dementia, hypertrophic episodes, optic nerve atrophy, optic nerve Retinopathy, cataract, hyperaldosteronemia, parathyroidism, myopathy, muscle atrophy, myoglobinuria, myotonia, muscle pain, exercise tolerance, tubulopathy, kidney failure, liver failure, liver failure, hepatomegaly, iron Erythrocyte anemia, neutropenia, hypoplatelet, diarrhea, chorionic atrophy, multiple vomiting, dysphagia, constipation, sensorineural hearing loss, mental retardation, epilepsy, and the like.

The term "treatment" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms, and the "preventing" means stopping or delaying the manifestation of a disease when used in a subject who does not exhibit symptoms but is at high risk. It means to let.

1 is a graph showing the results of measuring the amount of naphthoquinone compounds remaining in the plant, the ileum, and the large intestine when the one-pass intestinal perfusion method was performed according to Experimental Example 4;

2 is a graph showing the results of calculating the perfusion steady-state concentration at the outlet in Experimental Example 4.

Embodiment for Invention

Although the content of the present invention will be described with reference to the following Examples, the scope of the present invention is not limited thereto.

Experimental Example 1 Distribution Factor Measurement

Octanol and pH 7.4 phosphate buffer were saturated with relative solvents for at least 24 hours. A certain amount of naphthoquinone compound (Compound 1 in Table 1) was dissolved in saturated octanol, and mixed with tertiary distilled water, followed by stirring at 200 rpm using a magnetic stirrer for at least 13 hours. Each sample is taken, filtered with a 0.45 μm RC Membrane filter and diluted with methanol. This was analyzed by HPLC. The partition coefficient according to the amount of Compound 1 was measured and shown in Table 2 below.

TABLE 2

As shown in Table 2, it can be seen that the distribution coefficient is relatively fat soluble to 2.299. This means that it is about 100 times more soluble in octanol than in water and can be sufficiently absorbed through the hydrophobic layer inside the cell membrane.

Example 1 Refinement of Active Material Using Jet Mill

Micronization of the active material was achieved using a jet mill (Nisshin, SJ-100). Operation conditions were performed under the conditions of supply pressure 0.65 Mpa, feed rate 50-100 g / hr. 0.2 g of sodium lauryl sulfate (SLS) and 10 g of a naphthoquinone compound (Compound 1 in Table 1) were added, mixed, and ground. The micronized particles were recovered and measured for particle size using zeta potential, a particle counter. The average particle diameter of the particles was 1500 nm.

Example 2 Preparation of a Spray Dried Product

After adding the synthesized naphthoquinone compound (compound 1 of Table 1) or the naphthoquinone compound of Example 1 (including those not refined) to methylene chloride, salts such as sodium chloride, sucrose, lactose and the like Saccharides such as crystalline or microcrystalline cellulose, monocalcium phosphate, starch, mannitol, excipients such as magnesium stearate, talc, glyceryl behenate, solubilizers such as poloxamer, etc. After the addition, the mixture was well dispersed to prepare a spray drying liquid, which was spray dried.

Experimental Example 2 Elution of Spray Dry Formulation

The spray dried product of Example 2 was formulated so as to prevent disintegration by selecting an excipient such as water-soluble polymer (hydroxypropylmethylcellulose) and croscarmellose sodium, light anhydrous silicic acid, which are about the same amount as the active material. The elution test was performed in pH 6.8 buffer, and the elution rate was over 90% at 6 hours.

Experimental Example 3 Evaluation of Relative Bioavailability of Formulations

Ten Spraguelli rat males were attempted to assess the relative bioavailability in the fasted state using various formulations. Specifically, the naphthoquinone-based compound is roughly pulverized and added to an aqueous solution with 2% by weight of SLS (pre-crushing formulation), the naphthoquinone-based compound is pulverized with a jet mill to make fine particles, followed by aqueous solution with 2% by weight of SLS. To the formulation (powder after crushing), the spray dried product of Example 2 and the formulation of the excipient of Experimental Example 2 added to the aqueous solution (spray-drying formulation), and naphthoquinone-based compound was ground with a jet mill to fine particles After the formulation was made with the excipients, etc. of Experimental Example 2 and added to an aqueous solution (solid dispersion formulation) was used.

As a result of administration test by cross-over evaluation method with 50 mg / kg of active material in each group, blood concentration patterns as shown in Table 3 were obtained.

TABLE 3

As shown in the results of Table 3, the spray-dried formulation and the solid dispersion formulation added to the aqueous solution are about 3 times or more in the fasted state compared to the comparative formulation containing the same amount of the active material, in particular, the formulation before grinding It can be seen that the effect of improving the utilization rate.

Experimental Example 4 Comparison of Absorption Rate in the Field

To measure the intestinal absorption of naphthoquinone compounds, a single-pass intestinal perfusion method in the jejunum, ileum and large intestinal organs of rats intestinal perfusion technique).

The intestinal effective permeability (P _eff ) of the steady state may be expressed as follows.

_{P eff = [-Q in · ln} (C out / C in)] / A

-P _eff : Steady state intestinal effective permeability (cm / s)

Q _in : Perfusion flow rate (0.4 mL / min)

C _in , C _out : Inlet and fluid-transport-corrected outlet solution concentrations

A: Mass transfer surface area within intestinal segment (2πrL),

r, L: Radius and length of intestinal segment

The radius (r) and length (L) of the jejunum, ileum and large intestine used in the experiment are as follows: ( r : jejunum, 0.21 cm; ileum, 0.22 cm; large intestine, 0.23 cm, L: 10 cm).

Steady state was confirmed by the ratio of outlet concentration (C _out / C _in ) to inlet concentration versus time. Steady state is created when C _out / C _in of the naphthoquinone compound maintains a constant value (n = 3, error bars respect SD).

The results of measuring naphthoquinone compounds remaining in the three intestinal regions by time are shown in FIG. 1.

As shown in FIG. 1, a relatively large amount of naphthoquinone-based compound penetrated the intestinal tissue during the first 20 minutes, and remained almost indistinguishable thereafter. In addition, the bowel permeability was highest in the large intestine, and the transmittance was low in the order of the ileum and the plant.

The results of calculating the perfusion steady state concentration at the outlet are shown in Tables 4 and 2, respectively. Effective permeability was measured at four sites of intestinal tissue. As shown in Table 4 and Figure 2, it can be seen that the highest transmittance in the large intestine.

TABLE 4

Example 3 Preparation of Intestinal Target Formulation

The spray dried formulation prepared in Experimental Example 2 was added to an ethanol solution containing about 20% by weight of Eudragit S-100 as a pH sensitive polymer and about 2% by weight of PEG ＃ 6,000 as a plasticizer, followed by spray drying Intestinal target formulations were prepared.

Experimental Example 5 Acid Resistance

The enteric targeting formulation prepared in Example 3 was exposed to pH 1.2 and pH 6.8. After 6 hours, the intestinal target formulation was removed and washed and the content of active material was analyzed using HPLC. The amount of effective active material was evaluated as a measure of acid resistance, and the acid resistance was 90-100%, which is very good. Therefore, it is judged to be chemically stable in the stomach or small intestine.

Experimental Example 6 Measurement of Elution Rate

After exposure in an acidic environment of pH 1.2 as in Experimental Example 4, it was converted to pH 6.8 in an artificial environment. At this time, the residual amount of the eluted active material was measured by HPLC, and the results are shown in Table 5 below.

TABLE 5

Experimental Example 7 Effect of Intestinal Target Formulation

200 mg / kg each was injected into ob / ob mice once a day based on the content of the active material and the weight change was observed.

A 10-week-old obese, type 2 diabetic male male o b / ob mice (Jackson Lab) were purchased from Orient Co., Ltd. and adapted for 10 days and used in the experiment. The experimental diet used solid diet (P5053, Labdiet) as a basic diet. The ob / ob mice had a 10-day acclimation period with varying contrasts at 12-hour cycles based on 8 am and 8 pm in a breeding room with a temperature of 22 ㅁ 2 ℃ and a humidity of 55 ㅁ 5%. The ob / ob mice adapted to the environment were 10 mg / kg sodium lauryl sulfate administered control group, 200 mg / kg simple naphthoquinone compound administration group, and jet-mill pulverized naphthoquit according to the egg mass method. It was divided into non-system compound-administered group and intestinal-targeted drug-administered group of naphthoquinone-based compound which was subjected to grinding, divided into 7 mice per group at a dose of 200 mg / kg, and orally administered (PO), and water and feed were freely ingested. As shown in Table 6, it was confirmed that the weight loss result was significantly reduced in the intestinal-targeted drug administration group of the naphthoquinone-based compound subjected to the grinding process.

TABLE 6

As shown in Table 6, by showing the largest weight loss rate in the enteric-targeted drug administration group, it can be seen that excellent bioavailability was obtained.

As described above, the pharmaceutical composition for oral administration according to the present invention has the effect of improving the kinetic properties of the drug by increasing the amount of absorption in the body of the active material and increasing the duration of the body, resulting in a specific naphthoquinone compound Increasing the bioavailability can exert the desired pharmacological effect.

Those skilled in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above contents.

Claims (39)

A naphthoquinone-based compound represented by the following formula (1), a pharmaceutically acceptable salt, prodrug, solvate, or isomer thereof as an active material is formulated for enteric targeting, characterized in that:

Where R ₁ and R ₂ are each independently hydrogen, halogen, alkoxy, hydroxy or lower alkyl having 1 to 6 carbon atoms; R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently hydrogen, hydroxy, alkyl having 1 to 20 carbon atoms, alkene or alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Or two of these substituents may form a cyclic structure by mutual bonding, wherein the cyclic structure may be a saturated structure or a partially or wholly unsaturated structure; X is selected from the group consisting of C (R) (R '), N (R "), O and S, wherein R, R' and R" are each independently hydrogen or lower alkyl having 1 to 6 carbon atoms; n is 0 or 1, and when n is 0, its adjacent carbon atoms form a cyclic structure by direct bond. The pharmaceutical composition for oral administration according to claim 1, wherein X is O. According to claim 1, wherein the prodrug is a pharmaceutical composition for oral administration, characterized in that the compound represented by the formula (1a).

Where R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , X and n are the same as defined in Formula 1; R ₉ and R ₁₀ are each independently —SO _{3 —} Na ⁺ or a substituent or a salt thereof represented by the following Chemical Formula 2,

Where R ₁₁ and R ₁₂ are each independently hydrogen or substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl, R ₁₃ is selected from the group consisting of the following substituents iii) to iii), Iii) hydrogen; Ii) substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl; Iii) substituted or unsubstituted amine; Iii) substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or C ₃ -C ₁₀ heterocycloalkyl; Iii) substituted or unsubstituted C _{4 to} C ₁₀ aryl or C _{4 to} C ₁₀ heteroaryl; Iii)-(CRR'-NR "CO) _1- R ₁₄ , wherein R, R 'and R" are each independently hydrogen or substituted or unsubstituted linear or branched C ₁ -C ₂₀ alkyl, R ₁₄ May be selected from the group consisting of hydrogen, substituted or unsubstituted amine, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and 1 is selected from 1 to 5; Iii) substituted or unsubstituted carboxyl; Iii) -OSO _3- Na ⁺ ; k is selected from 0 to 20, and when k is 0, R ₁₁ and R ₁₂ are not present and R ₁₃ is directly bonded to a carbonyl group. The pharmaceutical composition for oral administration according to claim 1, wherein the compound of Formula 1 is selected from compounds of Formulas 3 and 4.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are the same as defined in Chemical Formula 1. The pharmaceutical composition for oral administration according to claim 1, wherein R ₁ and R ₂ are each hydrogen. According to claim 1, wherein the compound of formula 3 is a compound of formula 3a wherein R ₁ , R ₂ and R ₄ are each hydrogen, or R ₁ , R ₂ and R ₆ are each of the following formula 3b Pharmaceutical composition for oral administration

The pharmaceutical composition for oral administration according to claim 6, wherein the compound of Formula 4 is a compound of Formula 4a wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and R ₈ are each hydrogen:

The pharmaceutical composition for oral administration according to claim 1, wherein the formulation for enteric targeting is made by the addition of a pH sensitive polymer. According to claim 8, wherein the pH sensitive polymer is one or more selected from the group consisting of methacrylic acid-ethyl acrylate copolymer (Eudragit (registered trademark)) and hydroxypropyl methyl cellulose phthalate Pharmaceutical composition for oral administration characterized in that. 9. The pharmaceutical composition for oral administration according to claim 8, wherein the pH sensitive polymer is added via a coating. The pharmaceutical composition for oral administration according to claim 1, wherein the formulation for enteric targeting is made by the addition of a biodegradable polymer by enteric specific bacterial enzymes. The pharmaceutical composition for oral administration according to claim 11, wherein the polymer has an azo aromatic link. The pharmaceutical composition for oral administration according to claim 12, wherein the polymer having an azo aromatic bond is a copolymer of styrene and hydroxyethyl methacrylate (HEMA). The pharmaceutical composition for oral administration according to claim 11, wherein the polymer is a natural polysaccharide or a substituent thereof. 15. The oral cavity of claim 14, wherein the polysaccharide or a substituent thereof is at least one selected from the group consisting of dextran esters, pectin, amylose and ethylcellulose or pharmaceutically acceptable salts thereof. Pharmaceutical composition for administration. 2. The pharmaceutical composition for oral administration according to claim 1, wherein the formulation for enteric targeting is made by a biodegradable matrix by enteric specific bacterial enzymes. The pharmaceutical composition for oral administration according to claim 16, wherein the matrix is a synthetic hydrogel based on N-substituted acrylamide. The pharmaceutical composition for oral administration according to claim 1, wherein the intestinal targeting formulation is configured to release the drug after a predetermined lag time. The pharmaceutical composition for oral administration according to claim 18, wherein the delayed-time formulation is formed by the addition of a hydrogel. The pharmaceutical composition for oral administration according to claim 1, wherein the active material has a crystalline crystal structure. The pharmaceutical composition for oral administration according to claim 1, wherein the active material has a crystal structure of 50% or less in crystallinity. The pharmaceutical composition for oral administration according to claim 21, wherein the active material has an amorphous crystal structure. The pharmaceutical composition for oral administration according to claim 1, wherein the active material is included in the form of microparticles. The pharmaceutical composition for oral administration according to claim 23, wherein the microparticles have a particle diameter of 5 nm to 500 um. The pharmaceutical composition for oral administration according to claim 23, wherein the microparticles are made by spray drying or mechanical grinding of the active material. The pharmaceutical composition for oral administration according to claim 25, wherein the mechanical grinding is performed with a jet mill. The pharmaceutical composition for oral administration according to claim 23, wherein one or more substances selected from the group consisting of a surfactant, an antistatic agent and a hygroscopic agent are added in the microparticleing process. 28. The method of claim 27, wherein the surfactant is selected from the group consisting of anionic surfactants such as sodium docusate and sodium lauryl sulfate; Cationic surfactants such as benzalkonium chloride (Benzalkonium Chloride), benzetium chloride (Benzethonium Chloride), and cetrimide; Nonionic surfactants such as glycerin monooleate, polyoxyethylene sorbitan fatty acid esters, and sorbitan esters; Amphoteric polymers such as polyethylene-polypropylene polymers and polyoxyethylene-polyoxypropylene polymers (Poloxamer, Poloxamer), and other Gelucire ™ products; Monocaprylic Glycol Monocaprylate, Oleoyl Macrogol-6 Glyceride, Linoleoyl Macrogol-6-Glyceride , Group consisting of Caprylocaproyl macrogol-8 Glyceride, Propylene Glycol Monolaurate, and Polyglyceryl-6 Dioleate Pharmaceutical composition for oral administration, characterized in that one or two or more selected from. 28. The method of claim 27, wherein the moisture absorbent is colloidal silica, hard silicic anhydride, heavy silicic anhydride, sodium chloride, calcium silicate, potassium aluminosilicate, and calcium aluminosilicate, characterized in that one or more selected from the group consisting of. Pharmaceutical composition for oral administration. The pharmaceutical composition for oral administration according to claim 1, wherein in the preparation of the oral dosage form, a water-soluble polymer, a solubilizer and a disintegration accelerator are added. The pharmaceutical composition for oral administration according to claim 30, wherein the additives and the active material in the form of fine particles are mixed with a predetermined solvent and then spray-dried to form a pharmaceutical composition. The method of claim 30, wherein the water-soluble polymer is methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, hydroxy Pharmaceutical composition for oral administration, characterized in that one or more selected from the group consisting of propylmethylcellulose, hydroxypropylmethylcellulose phthalate, sodium carboxymethylcellulose, and carboxymethylethylcellulose. The pharmaceutical composition for oral administration according to claim 32, wherein the water soluble polymer is hydroxypropylmethylcellulose. 31. The method of claim 30, wherein the disintegration accelerator is one or more selected from the group consisting of sodium croscarmellose, crospovidone, calcium carboxymethyl cellulose, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. Pharmaceutical composition for oral administration characterized in that. The pharmaceutical composition for oral administration according to claim 34, wherein the disintegration promoter is sodium croscarmellose. 32. The pharmaceutical composition for oral administration according to claim 30, wherein the solubilizer is a surfactant or an amphoteric. The method of claim 30, wherein the water-soluble polymer is 10 to 1000 parts by weight, the disintegration accelerator is 1 to 30 parts by weight, the solubilizer is added to 0.1 to 20 parts by weight based on 100 parts by weight of the active material, respectively Pharmaceutical composition for administration. The method of claim 1, wherein the formulation for enteric targeting is (a) preparing an active material microparticle by grinding the naphthoquinone-based compound of Formula 1 alone or in a state where a surfactant and a moisture absorbent are added in a jet mill; (b) dissolving the active material fine particles in a predetermined solvent together with a water-soluble polymer, a solubilizing agent and a disintegration accelerator, and then spray-drying to prepare a formulation particle; (c) dissolving the formulation particles together with a pH-sensitive polymer and a plasticizer in a predetermined solvent, followed by spray drying to form an enteric target coating on the formulation particles; Pharmaceutical composition for oral administration, characterized in that through a process comprising a. The pharmaceutical composition for oral administration according to claim 1, wherein the active material exhibits a pharmacological effect on the treatment or prevention of metabolic diseases, degenerative diseases, and mitochondrial disorders.

Images